Obesity is a major health problem. For in spite of considerable effort by the scientific and healthcare professions to understand and successfully treat obesity, its incidence continues to rise and the obesity-related costs to society are staggering. The enormity of the problem is reflected in recent surveys and goals of the World Health Organization and the National Institutes of Health. The effort may soon be paying dividends, however, in that two factors have come to light in recent years that shed light on fundamental regulatory system that works to maintain a particular amount of fat in the body. This amount of fat may vary in different environments, and certainly varies considerably among individuals. Nonetheless, in a constant environment, individuals rigorously maintain and defend a particular amount of total stored energy in the form of fat. The second major factor that has come to light concerning human obesity is that when a diet with a high fat content is consumed on a regular basis, the amount of stored fat in the diet increases over time, as has occurred in many nations over the past thirty years, the incidence of obesity also increases. The key negative feedback system that regulates body fat slips. More fat is stored and the individual moves along the scale toward obesity. It is the interaction of these two factors that is the subject of this proposal. More specifically, over three interrelated projects, we ask how consumption of a high-fat diet modifies the negative feedback system that controls body fat. The driving hypothesis of this or any or all of several levels of control. Project 1 explores the processing of ingested fat by the gut and considers the generation and receptor of meal-related signals that control meal size. Project 2 investigates the generation and reception by the brain of adiposity-indicating signals. Finally, Project 3 considers brain neurotransmitter systems that control food intake and metabolism. Identifying the regulatory processes that mediate high-fat diet-induced obesity is the major goal of this project.